Recent Advances in the Treatment of Relapsed/Refractory Multiple Myeloma - Episode 4

Updates From the CANDOR Study in R/R Multiple Myeloma

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Katja Weisel, MD, leads a review of the study design and updated efficacy and safety results of the phase 3 CANDOR study for patients with relapsed/refractory multiple myeloma.

Nina Shah, MD: Katja, I want to focus for the next couple of minutes on different abstracts that have been presented that help fill out the discussion we’ve been having. Could you describe the design and updated efficacy and safety results of the CANDOR study? In this study, we’re comparing daratumumab–Kd [carfilzomib, dexamethasone] with Kd [carfilzomib, dexamethasone] in patients with relapsed/refractory multiple myeloma. The abstract was updated recently by Dr Meletios Dimopoulos. Maybe we can talk about the FDA or European approval of daratumumab–Kd [carfilzomib, dexamethasone] and how these results would affect clinical practice, some of the toxicities associated, how they’re managed, and an overview of this particular study.

Katja Weisel, MD: CANDOR was the milestone trial to get the approval, and the superiority which was expected for the triplet was already mirrored in the trial design as they chose a 2:1 randomization toward the triplet, the DKd [daratumumab, carfilzomib, dexamethasone] triplet vs the Kd [carfilzomib, dexamethasone] doublet. Patients from first to third relapse were included from the large phase 3 trials for early relapse. Patients were treated until disease progression or unacceptable toxicity. In the updated result, we saw in the primary report and publication that it maintained clear and met all the primary end points with a significant progression-free survival [PFS] benefit for carfilzomib-daratumumab-dexamethasone vs Kd [carfilzomib, dexamethasone], with a 28-month median PFS for DKd [daratumumab, carfilzomib, dexamethasone] vs 15 months for Kd [carfilzomib, dexamethasone]. This was highly significant.

An important point to make regarding the toxicity is that the addition of the monoclonal antibody didn’t lead to a significant addition of non-hematological toxicity and didn’t enhance cardiac events in the triplet arm. There’s always a trend toward more infections when we add the monoclonal anti-CD38. We know that, and it’s also partly an effect of the longer treatment resulting in that, but overall we saw a really well-tolerated regimen. This approval was founded on a very solid and strong database.

Nina Shah, MD: It’s interesting to see how well the control arm did, which in some ways was better than some of the experimental arms in previous studies with a similar design. You talked a little about how to get the right patients to the right treatment, and sometimes subgroup analyses can help us with that. Ola, I was wondering if you could talk about the results of the subgroup analysis of the CANDOR study by prior line of therapy, which was presented by Dr [Hang] Quach before and published in British Journal of Hematology. What are some key takeaways? Would the daratumumab–Kd [carfilzomib, dexamethasone] regimen be a treatment option in patients who had previously received carfilzomib or other particular therapies? What do you think?

Ola Landgren, MD, PhD: The CANDOR study is very powerful. But as you point out, Nina, it’s all about details, so looking at all these different aspects is very important to better understand what’s going on. This subgroup analysis was published in the British Journal of Hematology and looked at prior lines. Because this study was open for patients with 1 to 3 prior lines, the approach was to compare those patients who had 1 prior line with those who had 2 or more prior lines, so basically 1 vs 2 to 3. As far as the high points, No. 1 is the results look quite similar. There’s slightly worse efficacy for the sicker patients, which is in line with what happens with probably every drug. Usually drugs work better in early line.

But also there are subanalyses in this study looking at patients who had been exposed to and were refractory to both lenalidomide as well as PIs [proteasome inhibitor], bortezomib and ixazomib, and the results look very similar. It’s reassuring. The numbers get smaller when you start slicing it into smaller pieces, but the results are very consistent with the main result. This is an important paper.

Nina Shah, MD: Yes. We touched on this because Sagar mentioned daratumumab-bortezomib and dexamethasone. Katja, how did the CANDOR results compare with the CASTOR results where daratumumab–Vd [bortezomib, dexamethasone] was compared with Vd [bortezomib, dexamethasone]? You know this well because you were the lead author on this. What do you think about our apples-to-oranges comparison that we don’t like to do but we tend to do?

Katja Weisel, MD: It’s always a challenge to do a fair comparison. We have this clear interest to several reasons, but mainly 2 of them. They had to have prior comparison between bortezomib and carfilzomib-Vd [bortezomib, dexamethasone] and Kd [carfilzomib, dexamethasone]. There was a significant PFS and overall survival benefit for carfilzomib-dexamethasone in these head-to-head comparisons. The fair question to ask is, does that superiority somehow remain when you go into a triplet? We used a matching-adjusted indirect comparison analysis, which is the best you can do if you do a cross-trial analysis, where you try to exactly match the population that you analyze.

We saw a statistically significant superiority for DKd [daratumumab, carfilzomib, dexamethasone] vs DVd [daratumumab, bortezomib, dexamethasone], and this is the best you can do if you compare. It’s somehow also explainable. First, we know that carfilzomib is more potent in proteasome inhibition than bortezomib because it also overcomes potential bortezomib resistance. The other thing is that it allows a continuous application. This was a key issue in the CASTOR trial, that patients stopped the bortezomib after 8 cycles. We all know, even now with the experience we have with carfilzomib, that we can give it beyond 2 years to our patients. This is 1 thing, that we can remain with the combination over time in relapse disease. It’s part of the success for DKd [daratumumab, carfilzomib, dexamethasone].

Nina Shah, MD: Those are all important points in comparing the 2 trials, because you want to get an idea making these decisions. Sometimes these prospective trials aren’t fair to compare options.

Transcript Edited for Clarity